key: cord-0872418-pqmomulk
authors: Bray, Monica A.; Sartain, Sarah A.; Gollamudi, Jahnavi; Rumbaut, Rolando E.
title: MICROVASCULAR THROMBOSIS: EXPERIMENTAL AND CLINICAL IMPLICATIONS
date: 2020-05-23
journal: Transl Res
DOI: 10.1016/j.trsl.2020.05.006
sha: b75a8d84675bf1915cf26406721f9909c57e2463
doc_id: 872418
cord_uid: pqmomulk

Abstract A significant amount of clinical and research interest in thrombosis is focused on large vessels (e.g., stroke, myocardial infarction, deep venous thrombosis, etc.); however, thrombosis is often present in the microcirculation in a variety of significant human diseases, such as disseminated intravascular coagulation, thrombotic microangiopathy, sickle cell disease, and others. Further, microvascular thrombosis has recently been demonstrated in patients with COVID-19, and has been proposed to mediate the pathogenesis of organ injury in this disease. In many of these conditions, microvascular thrombosis is accompanied by inflammation, an association referred to as thromboinflammation. In this review, we discuss endogenous regulatory mechanisms that prevent thrombosis in the microcirculation, experimental approaches to induce microvascular thrombi, and clinical conditions associated with microvascular thrombosis. A greater understanding of the links between inflammation and thrombosis in the microcirculation is anticipated to provide optimal therapeutic targets for patients with diseases accompanied by microvascular thrombosis.

Thrombosis, or the pathologic formation of blood clots, is associated with a significant health and economic impact world-wide. A great deal of clinical and research attention on thrombosis focuses on arteries in common conditions such as stroke or myocardial infarction, or in veins such as in deep venous thrombosis. Thrombosis also affects the microcirculation with significant consequences; this review will focus on the connection between microvascular thrombosis pathogenesis and clinical implications. Microvascular thrombosis often occurs in diseases characterized not only by disordered clot formation but also by disordered inflammation. In fact, many of the diseases discussed in this review are characterized by a "loss of focality" or escape from regulation of the physiologic pathways involved in hemostasis and innate immunity. There is increasing awareness of the close association between inflammation and thrombosis, also referred to as "thromboinflammation." [1] The complex pathways of inflammation and coagulation appear to have a common evolutionary origin to defend against deadly insults. This is strikingly illustrated by the horseshoe crab, whose innate immune and coagulation systems are so intertwined that scientists consider them to be the same system. [2, 3] Going forward, a greater understanding of the mechanisms responsible in the links between thrombosis and inflammation is expected to aide in the design and development of more effective therapies for these conditions.

In a simplified manner, the microcirculation may be defined as those blood vessels that cannot be observed clearly by the human eye without assistance. [4] There are also some suggestions 9 of defining the microvasculature based on topography and hemodynamic responses, corresponding to a upper threshold of arteriole diameter of ~100 m [5] ; however, in reality there is no abrupt transition between macro-and microvessels but rather a gradual transition, thus each definition will have limitations. However, particularly when comparing the precapillary arterioles and post-capillary venules to large arteries and veins, there are clear structural and functional differences, discussed below.

The microvasculature is subdivided into three main categories of blood vessels: arterioles, capillaries and venules distinguished by location, function and structure. Sequentially the arterioles deliver oxygenated blood to the capillaries, which deliver oxygen to the parenchyma, then the venules collect deoxygenated blood from the capillaries. The arteriolar endothelium is surrounded by dense, circumferential smooth muscle cells; the capillary endothelium is surrounded by sparse pericytes and the venule endothelium is surrounded by sparse smooth muscle cells. [6] These cellular configurations are distinct from the three defined layers found in large vessels (intima, media, adventitia). Functionally, arterioles have a primary role of regulating distribution of blood flow, while the capillaries represent the primary site of fluid and solute exchange and the venules are the primary site of interaction with immune cells. The capillary beds do not hold a significant portion of the blood volume -estimated at less than 10% of the total volume -but have an enormous surface area for exchange. For example, morphometric analyses of human lungs estimate a capillary surface area of 126 m 2 [7] and total body skeletal muscle capillary surface area is estimated to far exceed 180 m 2 . [8, 9] To place these estimates in perspective, the sum of capillary surface area of lungs and skeletal muscle is larger than the area of a tennis court for doubles matches (nearly 261 m 2 ). There are densely 10 packed networks of capillaries throughout most organs, facilitating delivery of nutrients to surrounding tissues. Capillaries are in a unique position to directly exchange solutes and fluid with the parenchyma and also have the most organ-specific phenotypes within the vasculature. [10] The structure of microvasculature is influenced by biomechanical forces including shear stress and biochemical signals including hormones, growth factors, cytokines, chemokines, complement, and nitric oxide (NO) contribute to the unique highly adaptive microvascular endothelial cell phenotype. [11] While some features of endothelial cells are maintained in vitro, a significant amount are dependent on temporal and location specific signals. [11] [12] [13] Microvessels are subject to significantly increased wall shear stress, a tangential force exerted on vascular walls as a result of blood flow, as their size decreases. [14] Measures of mean wall shear stress in arterioles greatly exceed values in arteries within the same species. [14, 15] For example, within the same microvascular bed, mean wall shear stress measured in arterioles (>100 dyn/cm 2 for the smallest arterioles) exceeded that of venules of comparable diameter by about one order of magnitude. [16] Higher shear stress is deemed to contribute to significant morphologic differences of endothelial cells between arterioles and venules, with arteriolar endothelium appearing elongated in the direction of flow as compared to a cuboidal appearance of venular endothelium [17] ; this phenomenon is also well described in cultured endothelial cells. [18] Of note, blood rheology in the microcirculation is complex and does not follow the assumptions of traditional Newtonian flow; further, measures of microvessel hematocrit (an important determinant of viscosity and thus shear stress) by microscopy often yield values ≤50% than that of systemic hematocrit. [19, 20] These properties impact the 11 validity of wall shear stress measurements based on centerline blood flow velocity (a common experimental technique), although mathematical models have been developed to account for the unique environment. [21] In addition to the shear stress-induced differences in endothelial cell morphology between arterioles and venules, endothelium in these microvessels exhibit a variety of functional differences, including those exemplified in Figure 1 : leukocytes interact primarily with venular endothelium, and in some experimental models, a dramatic difference in von Willebrand factor expression.

Endothelial cells demonstrate wide heterogeneity in structure and function between microvessels and large blood vessels, between organs, within individual tissues, within regions of individual vascular networks, and as shown by single-cell analyses, also between cells of individual vessels; these differences are also obvious in the comparison of endothelial cells between healthy and diseased subjects. [22] [23] [24] In contrast to thrombosis in large arteries, thrombosis in microvessels can result in a more diffuse impairment of perfusion and widespread dysfunction of the affected organs.

Under resting conditions, the healthy microvascular endothelium is uniquely positioned to provide a powerful regulatory balance against similarly powerful stimuli predisposing to thrombosis. The resting endothelium provides an antiadhesive, anti-inflammatory, and antithrombotic barrier vital to maintaining homeostasis. Endothelial cells possess a broad range of endogenous regulatory mechanisms which can inhibit platelets, their adhesion to vascular walls, leukocyte-endothelial interactions, and/or the coagulation system. These are 12 discussed briefly below with an emphasis on the microcirculation; these concepts are reviewed in greater detail in other publications. [1, 25, 26] 1. Endothelial glycocalyx: this is a thin, flexible boundary layer between the phospholipid membrane of the endothelial cell and the cellular and macromolecule components of the blood. This endothelial surface layer provides the interface between flowing blood and endothelial cell membranes and represents a hydrodynamically significant layer.

The glycocalyx's constituents include proteoglycans, glycoproteins, and glycosaminoglycans containing heparan sulfate, chondroitin sulfate, hyaluronan and various core proteins (e.g., glypicans, syndecans, etc.). [27] These components, organized in a mesh-like array, provide a steric-and charge-dependent semipermeable barrier to fluid and solute transport and prevents blood cell adhesion to the endothelium. Measurement of the precise thickness of the endothelial glycocalyx is limited by its physicochemical characteristics which may alter its dimensions during preparation for ultrastructural studies. Using a variety of techniques, reported values of glycocalyx thickness in microvascular endothelium in vivo range from 0.1 to > 1 m [28] [29] [30] [31] . Although the endothelial glycocalyx is also present in large blood vessels, the hemodynamic implications of the glycocalyx are considerably greater in the microcirculation since it occupies a significant proportion of the vascular volume in microvessels with diameters as small as 5 m. While platelets are known to be activated by shear stress through several mechanisms [32] , shear stress on the endothelium induces a balancing effect. The endothelial glycocalyx is well recognized as a key mechanotransducer, mediating shear stress-dependent responses in endothelial 13 cells, including release of nitric oxide and prostacyclin [33] [34] [35] , which are endothelialderived inhibitors of platelets mentioned below. Experimental degradation of the endothelial glycocalyx has been shown to promote adhesion of platelets to microvascular endothelium [36, 37] . Preclinical models of conditions associated with thromboinflammation such as sepsis and ischemia/reperfusion injury have been shown to result in degradation of the endothelial glycocalyx [38, 39] . There is increasing interest in measurement of circulating and/or urinary glycocalyx components including syndecans, hyaluronan, heparan sulfate [40] [41] [42] [43] [44] as biomarkers in septic humans.

Further, a recent study reported an association between syndecan-1 levels and disseminated intravascular coagulation in patients with sepsis [45] . Overall, these studies suggest that degradation of the endothelial glycocalyx may contribute to the pathogenesis of certain thromboinflammatory conditions such as sepsis, and strategies aimed at preservation of the glycocalyx might represent future therapeutic targets in these conditions [46] .

2. Nitric oxide is a gaseous signaling molecule initially discovered as an endothelial-derived relaxing factor [47, 48] , but is now known to mediate a myriad of responses on a broad variety of cells. Endothelial cell nitric oxide synthase (eNOS) is one of three isoforms of NOS; while it is constitutively expressed, its activity may be regulated by various mechanisms including phosphorylation, protein-protein interactions, and subcellular localization, among others [49] . Microvascular endothelial cells release nitric oxide in response to hemodynamic forces mechanotransduced by the glycocalyx and several 14 agonists [50, 51] . Preclinical models suggest that endothelial release of nitric oxide provides endogenous protection against thrombosis and regulates inflammation through various mechanisms, including inhibition of endothelial adhesion molecule expression, release of P-selectin and von Willebrand factor, and inhibition of platelet activation. [52] [53] [54] Of interest to this review, mice with targeted deficiency of endothelial nitric oxide were reported to develop microvascular thrombosis in the kidney during aging [55] , comparable to thrombotic microangiopathy (TMA) discussed below. Modulating the regulatory functions of the microvascular endothelium, including nitric oxide, has been suggested as potential future therapeutic strategies for TMA. [56] 3. Prostacyclin: this product of arachidonic acid metabolism exerts several physiological responses comparable to those of nitric oxide. As in the case of nitic oxide, prostacyclin is released by microvascular endothelium in response to shear stress, resulting in vasodilatation as well as inhibition of platelet activation. [57] [58] [59] [60] Prostacyclin synthesis is dependent on cyclooxygenase-1 (COX-1, expressed constitutively) as well as an inducible form, COX-2.

[61] Endothelial cell-derived prostacyclin is presumed to be primarily dependent on cyclooxygenase-1 (COX-1); however, COX-1 is also expressed on platelets and mediates release of the prothrombotic molecule thromboxane A2. [62] Recent data generated from mice with cell-specific deletion of COX-1 and COX-2 have clarified the relative contribution of these enzymes in regulation of thrombotic tone in endothelial cells: endothelial cell COX-1 and COX-2 both prevent thrombosis, albeit via 15 distinct and complementary pathways. [63] From a clinical standpoint, the antithrombotic protection induced by low-dose aspirin (an inhibitor of COX-1 and COX-2) is presumed to reflect a balance favoring prostacyclin over thromboxane A2. [64] Prostacyclin has been approved for clinical use for pulmonary hypertension in the US since 1995, and isolated case reports of its off-label use for thrombotic microangiopathies describe conflicting findings. [65] [66] [67] A greater understanding of the role of cell-specific regulation of COX isoforms may provide insight into therapies targeting prostacyclin for microvascular thrombosis.

4. Other endothelial antithrombotic mechanisms: microvascular endothelial cells possess a variety of additional mechanisms that have been proposed to contribute to its endogenous antithrombotic properties. These include CD39/ectoADPase, a membrane bound enzyme that hydrolyzes adenosine triphosphate (ATP) and adenosine diphosphate (ADP) to adenosine monophosphate (AMP) and thus inhibits platelet activation. [68] Other antithrombotic molecules expressed in microvascular endothelium include tissue factor pathway inhibitor (TFPI) [69] , activated protein C, thrombomodulin [70] , and antithrombin. [71] Of interest, these molecules failed to improve outcomes in large clinical trials in patients with sepsis [72] [73] [74] [75] , including a trial focused on sepsis-induced coagulopathy in which thrombomodulin failed to demonstrate a clinical benefit. [75] Despite the failure of past large clinical trials performed on heterogenous groups of patients with sepsis, there is increased interest 16 in targeting these pathways in selected subsets of patients with microvascular thrombosis in sepsis and related thromboinflammatory disorders. [76] IV. Experimental models of microvascular thrombosis in vivo

Much of our understanding of the molecular mechanisms responsible for microvascular thrombosis is derived from preclinical studies utilizing intravital microscopy, or microscopy- Selected models are outlined very briefly below; for more in-depth discussion of this category of model, readers are referred to other reviews. [77, 78] 1. Physical and electrical models of microvascular injury: mechanical injury models are used commonly in preclinical studies in large vessels focusing on hemostasis (physiologic 17 cessation of blood flow following vascular injury), particularly transection of the tail to quantify bleeding time. [79] [80] [81] Physical injury models have also been used in the microcirculation, mostly decades ago, with techniques including micropuncture or vessel transection. [82] [83] [84] Thrombosis in these models occurs as a result of focal damage to microvascular endothelium and exposure of flowing blood to the subendothelium. While these physical models are relevant to hemostasis, challenges 3. Biochemical stimulation: a variety of biochemical agents have been applied topically to macro-and microvessels to induce thrombosis in vivo One common method involves topical application of ferric chloride, used commonly in microvessels like the carotid artery [102] [103] [104] as well as microvessels as in the mesentery [104] [105] [106] and quantifying thrombus formation by reduction in arterial flow and/or recruitment of platelets by intravital microscopy. The mechanism of thrombus formation is proposed to involve oxidant injury to endothelium with denudation [102, 103] , although recent findings suggest a more complex mechanism including participation of red cells. [107, 108] Despite the relative uncertainty of the mechanisms resulting in injury, ferric chloride remains a commonly used method to study thrombosis in vivo. Additionally, targeted agonists can be applied topically, such as histamine, calcium ionophore, adenosine diphosphate, among others. [109, 110] However, ferric chloride remains the most commonly utilized biochemical approach to study thrombosis and/or platelet recruitment in single vessels in vivo. In addition to agonists applied topically to microvessels, targeted agonists can also be administered systemically resulting in experimental models of disease associated with microvascular thrombi, which can be 20 utilized in pre-clinical evaluation of therapeutics. Some examples of these systemic agonists include lipopolysaccharide [111] , soluble von Willebrand factor [112] ,lectin concanavalin A (Con A) followed by anti-Con A [113] , among others.

An intriguing observation derived from several of the models described above is that the ultrastructural organization of microvascular thrombi is highly heterogenous. Several reports have demonstrated that microvascular thrombi in vivo and ex vivo contain a core area of tightly packed platelets with extensive shape change and frequent degranulation and a distal area containing loosely packed platelets with less evidence of activation. [84, 114, 115] This heterogeneity is deemed to be functionally significant, by influencing transport of biologically active substances across thrombi as well as thrombus stability [114, 115] , likely to have clinical implications. Figure Many of the experimental models of microvascular thrombosis described above result in platelet-rich thrombi, often with little evidence of fibrin by electron microscopy. [78] As described below, the structure of thrombi in clinical conditions associated with microvascular thrombosis varies considerably; for example, platelet-rich thrombi predominate in thrombotic thrombocytopenic purpura and fibrin-rich thrombi in hemolytic-uremic syndrome and disseminated intravascular coagulation. [117, 118] Similarly, the composition of thrombi in large vessels also varies according to vessel type and underlying disease [119] ; of interest, the 21 well-defined fibrin mesh often demonstrated in large vessel thrombi is not characteristic of the experimental microvascular thrombi described above.

1. Imaging of the microvasculature:

A key obstacle in effectively treating dysfunctional microvasculature is correctly identifying that there is an issue in that physiologic compartment. There have been significant advances in aids to the human eye, but the microvasculature continues to elude observation by many common clinical imaging techniques.

The resolution of a computed tomography angiogram or magnetic resonance angiogram typically does not provide information about the structure of these microscopic vessels. Even a conventional angiogram of the brain does not resolve vessels smaller than 500 µm. [ consumption but these findings lack specificity to aHUS. [165] In some cases it is clinically unclear whether the TMA is due to underlying TTP or HUS-the Mayo clinic consensus guidelines recommend initial TPE in these cases. [123] Additionally TMA- 33 complement-mediated with a positive anti-CFH autoantibody can benefit from TPE. [126] Eculizumab has been confirmed by phase 3 trials in children and adults to be superior to TPE alone and has significantly reduced the mortality and morbidity in this disease.

Earlier initiation (within one month of presentation) is associated with improved outcomes compared to months or years after presentation. [166, 167] TMA-complement mediated is a prime example of thromboinflammation, as immune overactivation directly leads to thrombosis. [1] The key therapeutic for this class, During physiologic hemostasis, the coagulation cascade is activated through the tissue factor pathway after the formation of platelet plug at sites of endothelial injury. This process, also known as secondary hemostasis, results in the generation of thrombin, which cleaves fibrinogen into fibrin, which then polymerizes into a stable fibrin plug. One study identified thrombomodulin mutations in 5% of aHUS patients who were 34 sequenced. [151] Thrombomodulin is a thrombin cofactor that negatively regulates coagulation activation and fibrinolysis. This study found that thrombomodulin also has regulatory roles in complement activation and binds to C3b and factor H in vitro. [151] Additionally thrombomodulin negatively regulates leukocyte trafficking. [169] Thrombomodulin provides one of many links between coagulation, complement and innate

immunity. An additional coagulation-based mutation identified in aHUS is diacylglycerol kinase epsilon (DGKE) which inhibits protein kinase C and plasminogen. [164, 170] Eculizumab is also used in this category but may be less effective than use in TMAcomplement mediated. [170] Currently, there is no specific treatment for this subtype of aHUS, but potential future directions could include pharmaceuticals that have been developed for DIC including recombinant thrombomodulin for patients with pathogenic thrombomodulin mutations. [75, 151] iii. TMA-Transplantation associated: Thrombotic microangiopathy has been observed after both solid organ and hematopoietic stem cell transplantation (HSCT). [171, 172] TMA after HSCT can affect any organ but typically involves the kidney, resulting in a similar phenotype to aHUS. [173] A prospective cohort identified proteinuria and hypertension as the earliest signs of TMA-TA; creatinine was also elevated but not 35 specific in comparison to HSCT recipients without TMA. [174] The diagnosis after HSCT is particularly challenging as many of the laboratory hallmarks of TMA are present at baseline, including schistocytes [175] , elevated lactate dehydrogenase (LDH) and thrombocytopenia. Severe inflammatory response with cytokine production [188] , activation of the complement system [189] and leukocytosis [190] . Indeed, germline mutations in the alternative complement pathway (Factor H, MCP/CD46, and Factor I) have been shown to predispose women to HELLP. [191, 192] There is literature suggesting that placental derived anti-angiogenic factors contribute to endothelial dysfunction and decreased renewal which results in platelet activation, hemolysis, and microvascular thrombosis. [193] The mainstay of treatment of HELLP is prompt delivery. [194] In addition, other therapies such as betamethasone for promoting fetal lung maturity, anti-hypertensives, magnesium sulfate for neuroprotection and supportive care with red blood cell or platelet transfusions are used prior to delivery. [195] Initially, corticosteroids were considered for treatment of HELLP based on the role of leukocytes in its pathophysiology [190, 196] , however their effect appears to be modest, with improved platelet recovery in those treated with corticosteroids and no effect on maternal-fetal outcomes. [197] Despite a role for complement activation, to date no major trials have been conducted 38 using eculizumab, however case report exists for its efficacy. [198] As we gain better understanding of pathogenesis of disease, more targeted treatments are expected to become available.

b. Disseminated intravascular coagulation (DIC): DIC is a different, but not mutually exclusive, category of microvascular occlusion than TMA. The fibrin-rich microvascular occlusions in DIC [111] are presumed to not allow for a significant percentage of RBCs to extrude through the occlusions resulting in anemia from characteristic mechanical damage. [124] Although schistocytes may be present in DIC, they tend to occur at a much lower frequency than in TMA. [199] Additionally, DIC is differentiated from TMA by widespread fibrin deposition resulting in low fibrinogen and coagulation cascade factor consumption leading to coagulopathy. [200, 201] Failure Assessment score of two points or more; one of the parameters being platelet count. [204] DIC in sepsis provides a clear connection between the innate immune system and the coagulation cascade. During healthy physiology, the innate immune system and the coagulation cascade cooperate to control infections at the source of inoculation. The innate immune system primarily attacks the invading organism, while the coagulation cascade helps contain the infected area with a fibrin meshpotentially contributing to an abscess capsule. [205, 206] The crosstalk between inflammation and thrombosis is extensive and covered by several reviews. [1, 207, 208] During sepsis, interactions between pathogen-associated patterns (PAMPs) and pattern recognition receptors (PRRs), including toll-like receptors (TLRs), on sentinel immune cells result 40 in increased production of a broad array of cytokines via transcription factor nuclear factor-kappa B (NK-kB) and mitogen activated protein (MAP) kinases. [209] Key cytokines released include tumor necrosis factor alpha (TNF-alpha), interleukin-1 (IL-1), interleukin-2 (IL-2), interleukin-6 (IL-6), and interleukin-8 (IL-8). [210] Sepsis is a highly heterogeneous syndrome [211] and therefore the path to DIC within sepsis may also be 1. Tissue Factor: The coagulation cascade has two primary pathways to activation: the contact activation pathway (intrinsic) and the tissue factor pathway (extrinsic). Tissue factor is expressed at a 41 high density on stationary cells protected from exposure to the soluble factor VII. [214, 215] In states of injury, tissue factor is exposed to the circulating components of the blood and aids in physiologic hemostasis. Tissue factor can also be expressed by stimulated monocytes, which has been demonstrated in animal and human models. [216, 217] Whether human platelets express tissue factor remains controversial. [216, 218] ii. DIC-Trauma: While the immediate mortality from severe trauma or "polytrauma" often arises from direct damage, such as hemorrhagic shock or primary brain injuries, delayed mortality is associated with secondary damage from the body's dysregulated response to injury and infection. Trauma patients can develop a systemic inflammatory response that can be complicated by DIC. [233] The excessive response to injury may also be followed by an excessive opposing response termed compensatory anti-inflammatory response syndrome (CARS). [234] In contrast to DIC-Sepsis with an initial PAMP-PRR interaction that can lead to self-induced DAMP-PRR interactions such as NETs, DIC-Trauma is characterized by initial DAMP-PRR interactions. One suggested contributory interaction in DIC-trauma is between mitochondrial DNA and TLR9, which also recognizes viral or bacterial DNA. immediate operations on fractures that can be temporarily addressed non-invasively. [234, 245] iii. DIC-Cancer: There has been a longstanding association between various types of malignancies and an increased incidence of thrombosis including arterial, venous and microvascular in the form of DIC. In some regards, malignancy may be viewed as even more heterogeneous than sepsis and trauma, so it is difficult to discuss pathogenesis under this broad category of disease. In infection, fibrin deposition functions to defend the body from an invader, but certain cancers may coop this physiologic function 45 to defend themselves from detection by the immune system. One study that analyzed cell lines from patients with pancreatic cancer found that some patients' cancer expressed TF microparticles into culture medium. [246] Another study in human breast cancer cells connected the upregulation of TF expression by nearby vascular endothelial cells as a marker for angiogenesis. [247] One study identified the presence of DIC in 6.8% of patients with solid tumors in three center cohort with independent risk factors of DIC including older age, male, advanced stage, breast cancer and the presence of necrosis on biopsy. [248] Fragmented red blood cells were also identified in approximately two thirds of the patients. Additionally, this study identified an increased considered, yet this is recommended with a low level of evidence by various society guidelines. [203] In contrast, the use of low molecular- 48 weight heparin for prevention of deep venous thrombosis in patients with DIC in the absence of bleeding or thrombocytopenia is generally recommended. [203, 263, 264] The management of DIC in patients with a predominant bleeding phenotype is beyond the scope of this review and is discussed elsewhere. [203] c These criteria emphasize the fulminant, rapidly progressive or "catastrophic" nature of CAPS as distinct from micro-vascular thrombi that may be observed in classic APS. The microvascular preference of CAPS and lack of significant coagulopathy (in contrast to DIC) can also create a clinical picture overlapping with TMA. [266] CAPS commonly involves the kidneys, skin, brain, cardiovascular 49 system, lung, and liver. [267] In classic APS the antibodies are considered pathogenic but not sufficient for disease. However, "triple positivity" with positive lupus anticoagulant, anti-cardiolipin and anti-beta-2-glycoprotein confers increased risk of developing thrombosis. [268] A "second hit" hypothesis has been proposed where existing antiphospholipid antibodies become pathogenic under inflammatory conditions leading to thrombus formation. [269] In vivo models of APS have used either mechanical, chemical or photochemical trauma or LPS to demonstrate increase in thrombosis in APL infused animals over the secondary trigger alone. [270, 271] [278] or clinical concern for microvascular complication, further testing with enzyme linked 51 immunosorbent assay for PF4-heparin complex and/or a functional assay such as serotonin release assay is recommended for further confirmation. [279] The HIT antibody binds to platelets via FcγRIIa receptors with resultant activation of tyrosine kinases including spleen tyrosine kinase (Syk) which results in platelet aggregation, release of procoagulant microparticles and granules. [280] [281] [282] [283] [284] In addition, HIT antibodies can induce expression of TF in monocytes [283] , activate neutrophils and promote formation of NETs which independently adds to the prothrombotic milieu. [285, 286] Treatment is primarily focused on avoidance of all heparin products and preventing and/or treating thrombosis with pharmaceuticals including direct thrombin inhibitors (such as bivalirudin and argatroban), danaparanoids, fondaparinux or rivaroxaban. [279] Anticoagulation with warfarin is usually not recommended prior to platelet recovery. The alternative anticoagulation is often continued at least until platelet recovery (in some cases up to 4 weeks) in those without thrombosis and up to 3-6 months for those with thrombosis, although optimal duration is unknown. [279, 287] With growing insight into the pathogenesis of disease, adjunctive treatments are being studied and considered. IVIG has been reported to be effective in selected refractory cases of HIT [288] and for prophylaxis in patients planned for heparin re-exposure. [ [307] , leukocytes [308] and coagulation cascade [309] . Free heme also 54 promotes NETosis [310] , IL-8 production [311] and inflammasome activation [312] . Initial observations of high levels of inflammation led to investigations of immunomodulatory medications for potential treatments. [328] More recent observations of an increased frequency of large vessel thrombosis has led to concern that the classically thrombotic pathways are also highly activated. 

The diseases characterized by microvascular thrombosis span a wide variety of medical specialties. In many conditions outlined in this review, microvascular thrombosis results 58 from uncontrolled activation of endogenous pathways aimed at protecting the host ( Figure 4 ). These powerful pathways require rigorous regulation to ensure they are unharnessed at the appropriate time, site, and duration; otherwise they may become extremely dangerous to the organism they are meant to protect. Despite the close links and common evolutionary origin of inflammation and thrombosis (as exemplified by the horseshoe crab), these pathways are often viewed separately in medical education and also through the historical separation of clinical disciplines (i.e., hematology, immunology, rheumatology, infectious disease, etc.). It is helpful to conceptualize inflammation and thrombosis as interconnected not only from a basic science perspective but also from a clinical perspective. A greater understanding of the nature of dysregulation of these inter-related pathways in disease is expected to help identify optimal targets for therapeutic intervention. Historically, the pattern of medicine involves describing a broad category of disease based on clinical similarities, which is then further subdivided into categories as different pathogeneses are discovered. This trend towards increased clinical resolution of pathogeneses could continue to an extreme where pathway dysregulation replaces the concept of diagnosis. As the future continues to trend toward personalized medicine, the ability to precisely define the nature of the dysregulation of these pathways in individual patients will help determine specific treatment dosing and duration to push the microvascular environment back into a self-regulating state. 

Thromboinflammation: challenges of therapeutically targeting coagulation and other host defense mechanisms

The molecular basis of innate immunity in the horseshoe crab

Coagulation and innate immune responses: can we view them separately?

Dilator response of rat mesenteric arcading arterioles to increased blood flow velocity

Molecular regulation of vessel maturation

The normal human lung: ultrastructure and morphometric estimation of diffusion capacity

Adolph Distinguished Lecture. Contemporary model of muscle microcirculation: gateway to function and dysfunction

Fine structure of the human skeletal muscle capillary. A morphometric analysis

Phenotypic heterogeneity of the endothelium: II

Phenotypic heterogeneity of the endothelium: I. Structure, function, and mechanisms

The in vivo endothelial cell translatome is highly heterogeneous across vascular beds

Interspecific scaling of blood flow rates and arterial sizes in mammals

Wall shear stress as measured in vivo: consequences for the design of the arterial system

Design principles of vascular beds

Endothelial gaps and permeability of venules in rat tracheas exposed to inflammatory stimuli

Flow-mediated endothelial mechanotransduction

Pulsatile magneto-hydrodynamic blood flows through porous blood vessels using a third grade non-Newtonian fluids model

Determination of capillary tube hematocrit during arteriolar microperfusion

Non-Newtonian flow of blood in arterioles: consequences for wall shear stress measurements

Endothelial cell heterogeneity. Cold Spring Harb Perspect Med

Single Cell Analysis in Vascular Biology

Organotypic vasculature: From descriptive heterogeneity to functional pathophysiology

Endogenous mechanisms of inhibition of platelet function

The Human Microcirculation: Regulation of Flow and Beyond

The endothelial glycocalyx: composition, functions, and visualization

Integrated Systems Physiology: from Molecule to Function to Disease. Platelet-Vessel Wall Interactions in Hemostasis and Thrombosis

The endothelial glycocalyx protects against myocardial edema

Effect of diabetes and hyaluronidase on the retinal endothelial glycocalyx in mice

The pulmonary endothelial glycocalyx regulates neutrophil adhesion and lung injury during experimental sepsis

Platelets and shear stress

The role of endothelial glycocalyx components in mechanotransduction of fluid shear stress

Fluid shear stress induces upregulation of COX-2 and PGI2 release in endothelial cells via a pathway involving PECAM-1, PI3K, FAK, and p38

Endothelial Glycocalyx-Mediated Nitric Oxide Production in Response to Selective AFM Pulling

Oxidized lipoproteins degrade the endothelial surface layer : implications for platelet-endothelial cell adhesion

Microvascular blood flow resistance: role of endothelial surface layer

A disintegrin and metalloproteinase 15-mediated glycocalyx shedding contributes to vascular leakage during inflammation

Antithrombin reduces shedding of the endothelial glycocalyx following ischaemia/reperfusion

Glycocalyx biomarker syndecan-1 is a stronger predictor of respiratory failure in patients with sepsis due to pneumonia, compared to endocan

Circulating heparan sulfate fragments mediate septic cognitive dysfunction

Evolution of serum hyaluronan and syndecan levels in prognosis of sepsis patients

Derangement of the endothelial glycocalyx in sepsis

Urinary Glycosaminoglycans Predict Outcomes in Septic Shock and Acute Respiratory Distress Syndrome

Circulating syndecan-1 predicts the development of disseminated intravascular coagulation in patients with sepsis

The glycocalyx: a novel diagnostic and therapeutic target in sepsis

The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine

Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor

Endothelial nitric oxide synthase in the microcirculation

Endothelial regulation of coronary microvascular tone under physiological and pathophysiological conditions

Loss of function in heparan sulfate elongation genes EXT1 and EXT 2 results in improved nitric oxide bioavailability and endothelial function

Nitric oxide regulates exocytosis by S-nitrosylation of N-ethylmaleimide-sensitive factor

Endogenous nitric oxide protects against thromboembolism in venules but not in arterioles

Endogenous nitric oxide protects against platelet aggregation and cyclic flow variations in stenosed and endothelium-injured arteries

Endothelial von Willebrand factor release due to eNOS deficiency predisposes to thrombotic microangiopathy in mouse aging kidney

The role of endothelial cell injury in thrombotic microangiopathy

Pulsatile flow increases the expression of eNOS, ET-1, and prostacyclin in a novel in vitro coculture model of the retinal vasculature

Prostacyclin (PGI2) inhibits the formation of platelet thrombi in arterioles and venules of the hamster cheek pouch

Endogenous nitric oxide and prostaglandins synergistically counteract thromboembolism in arterioles but not in venules

Exercise training enhances flow-induced vasodilation in skeletal muscle resistance arteries of aged rats: role of PGI2 and nitric oxide

Inducible COX-2 dominates over COX-1 in prostacyclin biosynthesis: mechanisms of COX-2 inhibitor risk to heart disease

Aspirin and the in vitro linear relationship between thromboxane A2-mediated platelet aggregation and platelet production of thromboxane A2

Cell-Specific Gene Deletion Reveals the Antithrombotic Function of COX1 and Explains the Vascular COX1/Prostacyclin Paradox

Role of nitric oxide and prostacyclin as vasoactive hormones released by the endothelium

Tacrolimus (FK 506) induced thrombotic thrombocytopenic purpura after ABO mismatched second liver transplantation: salvage with plasmapheresis and prostacyclin

Intravenous infusion of prostacyclin to prevent platelet thrombus during microvascular anastomoses

Unsuccessful treatment of resistant thrombotic thrombocytopenic purpura with prostacyclin

Identification and characterization of CD39/vascular ATP diphosphohydrolase

Tissue factor pathway inhibitor: structure-function

Crucial role of the protein C pathway in governing microvascular inflammation in inflammatory bowel disease

Endogenous antithrombin associated with microvascular endothelium. Quantitative analysis in perfused rat hearts

Efficacy and safety of tifacogin (recombinant tissue factor pathway inhibitor) in severe sepsis: a randomized controlled trial

Drotrecogin alfa (activated) in adults with septic shock

Caring for the critically ill patient

High-dose antithrombin III in severe sepsis: a randomized controlled trial

Effect of a Recombinant Human Soluble Thrombomodulin on Mortality in Patients With Sepsis-Associated Coagulopathy: The SCARLET Randomized Clinical Trial

A Systematic Summary of Systematic Reviews on Anticoagulant Therapy in Sepsis

Overview of murine thrombosis models

Microvascular thrombosis models in venules and arterioles in vivo

New approaches in tail-bleeding assay in mice: improving an important method for designing new anti-thrombotic agents

Abnormal platelet function in C3-deficient mice

Catalytic dysregulation of SHP2 leading to Noonan syndromes affects platelet signaling and functions

Both ADP and thrombin regulate arteriolar thrombus stabilization and embolization, but are not involved in initial hemostasis as induced by micropuncture

The effect of inhibition of prostaglandin synthesis on microvascular haemostasis and macromolecular leakage

Realtime detection of activation patterns in individual platelets during thromboembolism in vivo: differences between thrombus growth and embolus formation

Prostaglandin endoperoxides and thromboxane A2 in thrombus formation in the hamster cheek pouch in vivo

A study on the in vivo production of thrombosis in rat mesenteric arterioles and action of prostaglandin (PG) I2 on the thrombosis

Experimental thrombus formation in mesenteric microvessels: evaluation of a method

A Comparison of Vascular Smooth Muscle Reactivity, Thrombus Formation and Fragility in Response to Electrical Stimuli in the Hamster Cheek Pouch and Mesocaecum

Arterial thrombosis: relevance of a model with two levels of severity assessed by histologic, ultrastructural and functional characterization

Mouse cremaster venules are predisposed to light/dye-induced thrombosis independent of wall shear rate, CD18, ICAM-1, or P-selectin

Protein disulfide isomerase regulation by nitric oxide maintains vascular quiescence and controls thrombus formation

The disulfide isomerase ERp72 supports arterial thrombosis in mice

12(S)-HETrE, a 12-Lipoxygenase Oxylipin of Dihomo-gamma-Linolenic Acid, Inhibits Thrombosis via Galphas Signaling in Platelets

Novel Role for the AnxA1-Fpr2/ALX Signaling Axis as a Key Regulator of Platelet Function to Promote Resolution of Inflammation

RhoG protein regulates glycoprotein VI-Fc receptor gamma-chain complex-mediated platelet activation and thrombus formation

Differential role of von Willebrand factor and P-selectin on microvascular thrombosis in endotoxemia

Dysfunctional platelet membrane receptors: from humans to mice

Genome-wide RNA-seq analysis of human and mouse platelet transcriptomes

Of mice and not men: differences between mouse and human immunology

Nucleation of platelets with bloodborne pathogens on Kupffer cells precedes other innate immunity and contributes to bacterial clearance

Molecular mechanisms of NET formation and degradation revealed by intravital imaging in the liver vasculature

Ferric chloride-induced murine carotid arterial injury: A model of redox pathology

Rat model of arterial thrombosis induced by ferric chloride

Ferric Chloride-induced Thrombosis Mouse Model on Carotid Artery and Mesentery Vessel

Plasma Peptidylarginine Deiminase IV Promotes VWF-Platelet String Formation and Accelerates Thrombosis After Vessel Injury

Cathepsin G-dependent modulation of platelet thrombus formation in vivo by blood neutrophils

Resolving the multifaceted mechanisms of the ferric chloride thrombosis model using an interdisciplinary microfluidic approach

Red blood cells mediate the onset of thrombosis in the ferric chloride murine model

Platelets adhere to and translocate on von Willebrand factor presented by endothelium in stimulated veins

Inhibitory effect of caffeic acid on ADPinduced thrombus formation and platelet activation involves mitogen-activated protein kinases

A recombinant fragment of von Willebrand factor reduces fibrin-rich microthrombi formation in mice with endotoxemia

Formation and Resolution of Pial Microvascular Thrombosis in a Mouse Model of Thrombotic Thrombocytopenic Purpura

A murine model of site-specific renal microvascular endothelial injury and thrombotic microangiopathy

Platelet packing density is an independent regulator of the hemostatic response to injury

A systems approach to hemostasis: 4. How hemostatic thrombi limit the loss of plasma-borne molecules from the microvasculature

Serial block-face scanning electron microscopy reveals neuronal-epithelial cell fusion in the mouse cornea

Thrombotic thrombocytopenic purpura and hemolytic uremic syndrome are distinct pathologic entities. A review of 56 autopsy cases

Immunohistochemical study on the liver in autopsy cases with disseminated intravascular coagulation (DIC) with reference to clinicopathological analysis

The distinctive structure and composition of arterial and venous thrombi and pulmonary emboli

Primary angiitis of the central nervous system: diagnosis and treatment

Association of capillaroscopic microhaemorrhages with clinical and immunological antiphospholipid syndrome

The cumulative number of micro-haemorrhages and micro-thromboses in nailfold videocapillaroscopy is a good indicator of disease activity in systemic sclerosis: a validation study of the NEMO score

Thrombotic Microangiopathy Care Pathway: A Consensus Statement for the Mayo Clinic Complement Alternative Pathway-Thrombotic Microangiopathy (CAP-TMA) Disease-Oriented Group

The production of schistocytes by fibrin strands (a scanning electron microscope study)

Plasma exchange in thrombotic microangiopathies (TMAs) other than thrombotic thrombocytopenic purpura (TTP)

Guidelines on the Use of Therapeutic Apheresis in Clinical Practice -Evidence-Based Approach from the Writing Committee of the American Society for Apheresis: The Eighth Special Issue

Drug-associated thrombotic microangiopathies

Management of an acute outbreak of diarrhoeaassociated haemolytic uraemic syndrome with early plasma exchange in adults from southern Denmark: an observational study

Guidelines on the diagnosis and management of thrombotic thrombocytopenic purpura and other thrombotic microangiopathies

Heterogeneous pathogenic processes of thrombotic microangiopathies in patients with connective tissue diseases

Shear-induced unfolding triggers adhesion of von Willebrand factor fibers

Pathophysiology of thrombotic thrombocytopenic purpura

ADAMTS-13 conditions

Clinical practice. Thrombotic thrombocytopenic purpura

Transcriptional expression of tissue factor pathway inhibitor, thrombomodulin and von Willebrand factor in normal human tissues

Tissue distribution and regulation of murine von Willebrand factor gene expression in vivo

Differential Expression of CD31 and Von Willebrand Factor on

Endothelial Cells in Different Regions of the Human Brain: Potential Implications for Cerebral Malaria Pathogenesis

Derivation and external validation of the PLASMIC score for rapid assessment of adults with thrombotic microangiopathies: a cohort study

Efficacy and safety of first-line rituximab in severe, acquired thrombotic thrombocytopenic purpura with a suboptimal response to plasma exchange. Experience of the French Thrombotic Microangiopathies Reference Center

A phase 2 study of the safety and efficacy of rituximab with plasma exchange in acute acquired thrombotic thrombocytopenic purpura

Caplacizumab Treatment for Acquired Thrombotic Thrombocytopenic Purpura

Thrombotic microangiopathic hemolytic anemia with reduction of ADAMTS13 activity: initial manifestation of childhood-onset systemic lupus erythematosus

ADAMTS13 mutations and polymorphisms in congenital thrombotic thrombocytopenic purpura

Recombinant ADAMTS-13: first-in-human pharmacokinetics and safety in congenital thrombotic thrombocytopenic purpura

Acquired ADAMTS-13 deficiency in pediatric patients with severe sepsis

Prognostic value of ADAMTS13 in patients with severe sepsis and septic shock

Microangiopathic haemolytic anaemia resembling thrombotic thrombocytopenic purpura in systemic lupus erythematosus: the role of ADAMTS13

Treatment with or without plasma exchange for patients with acquired thrombotic microangiopathy not associated with severe ADAMTS13 deficiency: a propensity score-matched study

Brain microvascular endothelial cells exhibit lower activation of the alternative complement pathway than glomerular microvascular endothelial cells

TNF Regulates Essential Alternative Complement Pathway Components and Impairs Activation of Protein C in Human Glomerular Endothelial Cells

Thrombomodulin mutations in atypical hemolytic-uremic syndrome

Verotoxin-binding in human renal sections

Shiga-toxin-producing Escherichia coli and haemolytic uraemic syndrome

Eculizumab treatment in severe pediatric STEC-HUS: a multicenter retrospective study

The risk of the hemolytic-uremic syndrome after antibiotic treatment of Escherichia coli O157:H7 infections

Thomsen-Friedenreich antigen in haemolytic-uraemic syndrome

Haemolytic uraemic syndrome and the Thomsen Friedenreich antigen

Hemolytic Uremic Syndrome and Streptococcus Pneumoniae: Improving our Understanding

Autoimmune hemolytic anemia

Complement in disease: a defence system turning offensive

Relative role of genetic complement abnormalities in sporadic and familial aHUS and their impact on clinical phenotype

Pathology of renal diseases associated with dysfunction of the alternative pathway of complement: C3 glomerulopathy and atypical hemolytic uremic syndrome (aHUS)

Tissue-specific host recognition by complement factor H is mediated by differential activities of its glycosaminoglycan-binding regions

Comprehensive genetic analysis of complement and coagulation genes in atypical hemolytic uremic syndrome

Diagnostic Utility of Complement Serology for Atypical Hemolytic Uremic Syndrome

Eculizumab is a safe and effective treatment in pediatric patients with atypical hemolytic uremic syndrome

Terminal Complement Inhibitor Eculizumab in Adult Patients With Atypical Hemolytic Uremic Syndrome: A Single-Arm, Open-Label Trial

Eculizumab and Beyond: The Past, Present, and Future of Complement Therapeutics

The lectin-like domain of thrombomodulin confers protection from neutrophil-mediated tissue damage by suppressing adhesion molecule expression via nuclear factor kappaB and mitogenactivated protein kinase pathways

Recessive mutations in DGKE cause atypical hemolytic-uremic syndrome

De novo thrombotic microangiopathy after non-renal solid organ transplantation

Transplantassociated microangiopathy in patients receiving tacrolimus following allogeneic stem cell transplantation: risk factors and response to treatment

Hematopoietic Stem Cell Transplant-Associated Thrombotic Microangiopathy

Diagnostic and risk criteria for HSCT-associated thrombotic microangiopathy: a study in children and young adults

Clinical significance of fragmented red cells after allogeneic bone marrow transplantation

Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome following allogeneic HPC transplantation: a diagnostic dilemma

The alternative complement pathway activation product Ba as a marker for transplant-associated thrombotic microangiopathy

Abnormalities in the alternative pathway of complement in children with hematopoietic stem cell transplantassociated thrombotic microangiopathy

Therapeutic Plasma Exchange does not Improve Renal Function in Hematopoietic Stem Cell Transplantation-Associated Thrombotic Microangiopathy: An Institutional Experience

Eculizumab therapy in children with severe hematopoietic stem cell transplantation-associated thrombotic microangiopathy

Thrombotic Microangiopathy after Allogeneic Stem Cell Transplantation: A Comparison of Eculizumab Therapy and Conventional Therapy

Drug-induced thrombotic microangiopathy: a systematic review of published reports

Liver disease in pregnancy

Diagnosis and Management of HELLP Syndrome Complicated by Liver Hematoma

Hepatic histopathologic condition does not correlate with laboratory abnormalities in HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet count)

HELLP syndrome: the state of the art

Emerging new biomarkers of preeclampsia

Nuclear transcription factorkappa beta-dependent ultrastructural alterations within the placenta and systemic inflammatory activation in pregnant patients with hemolysis, elevated liver functions and low thrombocyte count (HELLP) syndrome: a case-control study

Direct evidence of complement activation in HELLP syndrome: A link to atypical hemolytic uremic syndrome

Leukocytosis is proportional to HELLP syndrome severity: evidence for an inflammatory form of preeclampsia

Germline mutations in the alternative pathway of complement predispose to HELLP syndrome

Factor H, membrane cofactor protein, and factor I mutations in patients with hemolysis, elevated liver enzymes, and low platelet count syndrome

Advances in understanding of pathogenesis of aHUS and HELLP

Diagnosis, controversies, and management of the syndrome of hemolysis, elevated liver enzymes, and low platelet count

Report of the American College of Obstetricians and Gynecologists' Task Force on Hypertension in Pregnancy

HELLP syndrome is associated with an increased inflammatory response, which may be inhibited by administration of prednisolone

Corticosteroids for HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome in pregnancy

Eculizumab, a novel potential treatment for acute kidney injury associated with preeclampsia/HELLP syndrome

Schistocytes in disseminated intravascular coagulation

Coagulation findings in the hemolytic-uremic syndrome of infancy: similarity to hyperacute renal allograft rejection

Profiles of Coagulation and Fibrinolysis Activation-Associated Molecular Markers of Atypical Hemolytic Uremic Syndrome in the Acute Phase

Towards definition, clinical and laboratory criteria, and a scoring system for disseminated intravascular coagulation

Diagnosis and treatment of disseminated intravascular coagulation (DIC) according to four DIC guidelines

The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3)

Protease-Mediated Growth of Staphylococcus aureus on Host Proteins Is opp3 Dependent

Contribution of Staphylococcus aureus Coagulases and Clumping Factor A to Abscess Formation in a Rabbit Model of Skin and Soft Tissue Infection

Inflammation and coagulation

Tissue factor as a link between inflammation and coagulation

Pathogen recognition and Toll-like receptor targeted therapeutics in innate immune cells

The pathophysiology and treatment of sepsis

A Multicenter Network Assessment of Three Inflammation Phenotypes in Pediatric Sepsis-Induced Multiple Organ Failure

Disseminated intravascular coagulation

Disseminated intravascular coagulation: an update on pathogenesis and diagnosis

Selective cellular expression of tissue factor in human tissues. Implications for disorders of hemostasis and thrombosis

Localization of human tissue factor antigen by immunostaining with monospecific, polyclonal anti-human tissue factor antibody

Tissue Factor: An Essential Mediator of Hemostasis and Trigger of Thrombosis

The in vivo kinetics of tissue factor messenger RNA expression during human endotoxemia: relationship with activation of coagulation

Detection of tissue factor in platelets: why is it so troublesome?

Regulation of tissue factor gene expression in monocytes and endothelial cells: Thromboxane A2 as a new player

Why have clinical trials in sepsis failed?

Neutrophil extracellular traps induce aggregation of washed human platelets independently of extracellular DNA and histones

Histone induced platelet aggregation is inhibited by normal albumin

Histones stimulate von Willebrand factor release in vitro and in vivo

Neutrophil extracellular traps promote thrombin generation through platelet-dependent and platelet-independent mechanisms

The role of extracellular DNA and DNA-binding proteins in the pathogenesis of DIC

Extracellular DNA traps promote thrombosis

von Willebrand factor directly interacts with DNA from neutrophil extracellular traps

Reciprocal coupling of coagulation and innate immunity via neutrophil serine proteases

Neutrophil extracellular traps in immunity and disease

Monocytes, neutrophils, and platelets cooperate to initiate and propagate venous thrombosis in mice in vivo

Neutrophil extracellular traps promote deep vein thrombosis in mice

Host DNases prevent vascular occlusion by neutrophil extracellular traps

Disseminated intravascular coagulation and sustained systemic inflammatory response syndrome predict organ dysfunctions after trauma: application of clinical decision analysis

Toll-like receptor signal transduction

Circulating mitochondrial DAMPs cause inflammatory responses to injury

Postinjury Inflammation and Organ Dysfunction

Defibrination after brain-tissue destruction: A serious complication of head injury

Significant correlations between tissue factor and thrombin markers in trauma and septic patients with disseminated intravascular coagulation

Systemic activation of tissuefactor dependent coagulation pathway in evolving acute respiratory distress syndrome in patients with trauma and sepsis

Classifying types of disseminated intravascular coagulation: clinical and animal models

Plasminogen activator inhibitor 1 (PAI-1): in vitro activities and clinical relevance

Plasminogen activator and plasminogen activator inhibitor I release during experimental endotoxaemia in chimpanzees: effect of interventions in the cytokine and coagulation cascades

Differentiating disseminated intravascular coagulation (DIC) with the fibrinolytic phenotype from coagulopathy of trauma and acute coagulopathy of trauma-shock (COT/ACOTS)

Therapeutical Strategies and Outcome of

Polytraumatized Patients with Pelvic InjuriesA Six-Year Experience

Tumor-derived tissue factor activates coagulation and enhances thrombosis in a mouse xenograft model of human pancreatic cancer

In situ detection of tissue factor in vascular endothelial cells: correlation with the malignant phenotype of human breast disease

Disseminated intravascular coagulation in solid tumors: clinical and pathologic study

Review of haemophagocytic lymphohistiocytosis

HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis

Coagulation Disorders and Bleedings in Critically Ill Patients With Hemophagocytic Lymphohistiocytosis

Histopathology of the liver in histiocytosis syndromes

Pathology of the liver in familial hemophagocytic lymphohistiocytosis

Highly elevated ferritin levels and the diagnosis of hemophagocytic lymphohistiocytosis

Confirmed efficacy of etoposide and dexamethasone in HLH treatment: long-term results of the cooperative HLH-2004 study

Clinical features, treatment, and outcome of macrophage activation syndrome complicating systemic juvenile idiopathic arthritis: a multinational, multicenter study of 362 patients

Emapalumab in Children with Primary Hemophagocytic Lymphohistiocytosis

Evidence-based diagnosis and treatment of macrophage activation syndrome in systemic juvenile idiopathic arthritis

Benefit of Anakinra in Treating Pediatric Secondary Hemophagocytic Lymphohistiocytosis

A randomized, controlled, multicenter trial of the effects of antithrombin on disseminated intravascular coagulation in patients with sepsis

A comparative double-blind randomized trial of activated protein C and unfractionated heparin in the treatment of disseminated intravascular coagulation

Human Soluble Recombinant Thrombomodulin, ART-123, Resolved Early Phase Coagulopathies, but Did Not Significantly Alter the 28 Day Outcome in the Treatment of DIC Associated with Infectious Systemic Inflammatory Response Syndromes

Prophylactic heparin in patients with severe sepsis treated with drotrecogin alfa (activated)

Supportive management strategies for disseminated intravascular coagulation

International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS)

Catastrophic antiphospholipid syndrome

Diagnosis and management of catastrophic antiphospholipid syndrome

Clinical course of high-risk patients diagnosed with antiphospholipid syndrome

Pathogenesis of antiphospholipid syndrome: understanding the antibodies

Thrombogenic properties of murine anti-cardiolipin antibodies induced by beta 2 glycoprotein 1 and human immunoglobulin G antiphospholipid antibodies

Thrombogenicity of beta 2-glycoprotein I-dependent antiphospholipid antibodies in a photochemically induced thrombosis model in the hamster

Antiphospholipid antibodies promote leukocyte-endothelial cell adhesion and thrombosis in mice by antagonizing eNOS via beta2GPI and apoER2

Complement activity and complement regulatory gene mutations are associated with thrombosis in APS and CAPS

The effect of triple therapy on the mortality of catastrophic anti-phospholipid syndrome patients

Rituximab use in the catastrophic antiphospholipid syndrome: descriptive analysis of the CAPS registry patients receiving rituximab

Free flap loss caused by heparin-induced thrombocytopenia and thrombosis (HITT): a case report and literature review

Heparin-induced skin lesions and other unusual sequelae of the heparin-induced thrombocytopenia syndrome: a nested cohort study

Predictive value of the 4Ts scoring system for heparin-induced thrombocytopenia: a systematic review and meta-analysis

American Society of Hematology 2018 guidelines for management of venous thromboembolism: heparin-induced thrombocytopenia

Heparinplatelet activation through FcgammaRIIA

Sera from patients with heparin-induced thrombocytopenia generate platelet-derived microparticles with procoagulant activity: an explanation for the thrombotic complications of heparin-induced thrombocytopenia

PRT-060318, a novel Syk inhibitor, prevents heparin-induced thrombocytopenia and thrombosis in a transgenic mouse model

The Syk-kinase inhibitor R406 impairs platelet activation and monocyte tissue factor expression triggered by heparin-PF4 complex directed antibodies

Activation of Fc gamma RII induces tyrosine phosphorylation of multiple proteins including Fc gamma RII

Neutrophil activation and NETosis are the major drivers of thrombosis in heparin-induced thrombocytopenia

Neutrophil accumulation and NET release contribute to thrombosis in HIT

Treatment and prevention of heparin-induced thrombocytopenia: Antithrombotic Therapy and Prevention of Thrombosis

Autoimmune heparin-induced thrombocytopenia

Heparin-associated thrombocytopenia: alternative managements

Plasmapheresis and heparin reexposure as a management strategy for cardiac surgical patients with heparin-induced thrombocytopenia

Pathogenesis and treatment of sickle cell disease

Pathophysiology of Sickle Cell Disease

Treatment and prevention of pain due to vaso-occlusive crises in adults with sickle cell disease: an educational void

Sickle cell biomechanics

Primary role for adherent leukocytes in sickle cell vascular occlusion: a new paradigm

Delay time of hemoglobin S polymerization prevents most cells from sickling in vivo

Kinetics of sickle cell biorheology and implications for painful vasoocclusive crisis

Sickle erythrocyte adherence to endothelium at low shear: role of shear stress in propagation of vaso-occlusion

Heterogeneous red blood cell adhesion and deformability in sickle cell disease

Sickle red cell-endothelium interactions

Platelet activation in patients with sickle disease, hemolysis-associated pulmonary hypertension, and nitric oxide scavenging by cell-free hemoglobin

Silent cerebral infarcts: a review on a prevalent and progressive cause of neurologic injury in sickle cell anemia

Neutrophil AKT2 regulates heterotypic cell-cell interactions during vascular inflammation

Neutrophils, platelets, and inflammatory pathways at the nexus of sickle cell disease pathophysiology

The contribution of endothelial cell P-selectin to the microvascular flow of mouse sickle erythrocytes in vivo

Critical role of endothelial cell activation in hypoxia-induced vasoocclusion in transgenic sickle mice

Erythroid DAMPs drive inflammation in SCD

Heme triggers TLR4 signaling leading to endothelial cell activation and vaso-occlusion in murine sickle cell disease

Interplay between coagulation and vascular inflammation in sickle cell disease

Heme-related molecules induce rapid production of neutrophil extracellular traps

Neutrophil activation by heme: implications for inflammatory processes

Hemolysis-induced lethality involves inflammasome activation by heme

Pulmonary thrombotic arteriopathy in patients with sickle cell disease

Stroke in a cohort of patients with homozygous sickle cell disease

Lung vasoocclusion in sickle cell disease mediated by arteriolar neutrophil-platelet microemboli

Physicians' attitude and practices in sickle cell disease pain management

Hydroxyurea and a cGMP-amplifying agent have immediate benefits on acute vaso-occlusive events in sickle cell disease mice

Novel Sickle Cell Disease Therapies: Targeting Pathways Downstream of Sickling

Randomized Trial of Voxelotor in Sickle Cell Disease

Randomized phase 2 study of GMI-1070 in SCD: reduction in time to resolution of vaso-occlusive events and decreased opioid use

MEK1/2 inhibitors reverse acute vascular occlusion in mouse models of sickle cell disease

Long-term results of related myeloablative stem-cell transplantation to cure sickle cell disease

Gene Therapy in a Patient with Sickle Cell Disease

Nervous system involvement in Degos disease

Pediatric Malignant Atrophic Papulosis

Degos disease: a C5b-9/interferon-alpha-mediated endotheliopathy syndrome

Treprostinil increases the number and angiogenic potential of endothelial progenitor cells in children with pulmonary hypertension

Tocilizumab treatment in COVID-19: A single center experience

Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia

Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: a report of five cases